POS0328 AUTOPHAGY MODULATION BY TOFACITINIB IMPROVES PSORIATIC ARTHRITIS FIBROBLAST-LIKE SYNOVIOCYTES FUNCTION.
Authors: E. Silvagni, S. Missiroli, S. Patergnani, C. Boncompagni, M. S. Ciliento, G. Lanza, M. Perrone, A. Bortoluzzi, M. Govoni, C. Giorgi, C. A. Scirè, P. Pinton
Journal: Annals of the Rheumatic Diseases (2022)

Background Psoriatic arthritis (PsA) is a chronic inflammatory systemic disease, and peripheral joints involvement is responsible of significant morbidity for patients, leading to damage accrual. Different drugs are available for the systemic management of this condition, with different mechanisms of action. Nevertheless, the rules driving the correct therapeutical choice in each individual patient are not completely defined. Janus kinases (JAK) inhibitors are a class of drugs able to reduce synovial inflammation, and tofacitinib, a JAK1/3 inhibitor, is the most studied. Preliminary evidence suggest an effect of tofacitinib on fibroblast-like synoviocytes (FLS) from PsA patients, reducing pro-invasive and pro-inflammatory properties. The link between JAK inhibition and FLS function improvement at synovial level is not fully understood. Objectives To evaluate the effect of tofacitinib on spontaneous autophagic activity of PsA FLS, and to confirm its effect on anti-inflammatory and anti-invasive properties of PsA FLS and synovial explants. Methods This is an in vitro study. Patients with active PsA underwent ultrasound-guided synovial biopsy. Histological evaluation was performed according to Krenn’s synovitis score. FLS, PBMCs and synovial explants cultures were set up, and cells were treated in vitro with tofacitinib 1 µM or vehicle control for 24h. Protein levels in cellular homogenates were analysed by western blot for relevant autophagy markers. Autophagy was also studied by fluorescence microscopy using GFP-LC3. Chemokines/cytokines levels into culture supernatants were quantified by ELISA. Migration assays were used to investigate the effect of tofacitinib on invasive properties of FLS. Differences were determined adopting the non-parametric Wilcoxon signed rank test. Results 16 patients with moderately active PsA were enrolled (Table 1). Mean (SD) Krenn’s synovitis score was 4.4. (1.9). Tofacitinib significantly increased LC3-II and ATG7 levels in PsA FLS compared to vehicle control, while p62 levels were not significantly affected, suggesting an increase in spontaneous autophagy activity, confirmed by LC3-autophagic vesicles count (Figure 1). No effect was highlighted in PBMCs and synovial explants cultures. Tofacitinib significantly reduced migration properties of PsA FLS, as well as MCP-1 and IL-6 release into FLS and synovial explants cultures supernatants. Table 1. Baseline demographic and clinical data of included patients (N=16). Variables Frequency Age (years), mean (SD) 59.8 (7.9) Female, N (%) 5 (31.3%) Disease duration (years), mean (SD) 9.7 (7.9) CRP (mg/dl), mean (SD) 1.5 (2.0) Patient Global Activity (0-100), mean (SD) 73.4 (16.9) Physician Global Activity (0-100), mean (SD) 56.3 (18.1) DAPSA, mean (SD) 25.6 (6.8) HAQ (0-3), mean (SD) 0.9 (0.5) Previous csDMARDs treatment, N (%) 13 (81.3%) Previous bDMARDs treatment, N (%) 6 (37.5%) Grey scale synovitis - joint to be biopsied (0-3), mean (SD) 1.9 (0.8) Joint effusion - joint to be biopsied (0-3), mean (SD) 1.4 (0.7) Power Doppler - joint to be biopsied (0-3), mean (SD) 0.5 (0.6) Krenn’s synovitis score (0-9), mean (SD) 4.4 (1.9) Abbreviations: SD, standard deviation; CRP, C reactive protein; DAPSA, Disease Activity Index for Psoriatic Arthrititis; HAQ, Health Assessment Questionnaire; csDMARD, conventional synthetic disease modifying antirheumatic drugs; bDMARD, biological disease modifying antirheumatic drugs. Figure 1. Tofacitinib significantly increased LC3-II and ATG7 levels in PsA FLS homogenates (A), and LC3-autophagic vesicles (B). Tofacitinib significantly reduced MCP-1 and IL-6 release into FLS cultures supernatants (C), and reduced PsA FLS migration properties at 24h (D). Conclusion The induction of autophagy by tofacitinib might permit a better functioning of PsA FLS, with a coherent reduction in pro-invasive and pro-inflammatory properties. This may contribute to the rationale for tofacitinib use in PsA management. References [1]Gao Ann Rheum Dis. 2016 Jan;75(1):311-5 [2]O’Brien Front Immunol. 2021 Jun 24;12:672461. Disclosure of Interests Ettore Silvagni Grant/research support from: E. Silvagni has received research support from AbbVie., Sonia Missiroli: None declared, Simone Patergnani: None declared, Caterina Boncompagni: None declared, Maria Sofia Ciliento: None declared, Giovanni Lanza: None declared, Mariasole Perrone: None declared, Alessandra Bortoluzzi: None declared, Marcello Govoni: None declared, Carlotta Giorgi: None declared, Carlo Alberto Scirè Grant/research support from: C.A. Scirè has received research support from AbbVie., Paolo Pinton: None declared